Abstract Treatment of focal segmental glomerulosclerosis (FSGS) is primarily empiric, often inadequate, results in moribity that typically progresses to renal failure and dialysis. FSGS frequently recurres rapidly post transplant. A circulating Permeability Factor (PF) has been suspected as central to the pathogenesis of some forms of FSGS but its identity has been difficult to discern. Corticosteroids are the first line of treatment for FSGS but other immunosuppressive drugs including cyclosporine, cyclophosphamide, plasmapheresis, protein A immunoabsorption, and mycophenolate mofetil have been tried with variable efficacy. The efficacy of these drugs suggests that some cases of FSGS have an autoimmune component. Treatment with rituximab, a chimeric mouse/human monoclonal antibody directed against the human CD20 antigen expressed on B-cells results in rapid reversible elimination of B-cells, a depletion that lasts for 6 to 12 months. We have treated a pediatric renal transplant patient, who had developed a rapid recurrence of FSGS, with rituximab for a post transplant lymphoma. Following this treatment, the FSGS-associated proteinuria resolved and the patient remains in remission for both PTLD and FSGS at one year. Our case and several similar cases recently reported in the literature leads to our novel hypothesis that at least some cases of FSGS have a B-cell autoimmune component as part of the disease pathophysiology. We will test this hypothesis within the context of two specific aims: Aim 1. Conduct a pilot trial to determine the preliminary efficacy, safety and tolerability of rituximab in the treatment of steroid resistant FSGS. Aim 2. Compare pharmacokinetic/pharmacodynamic assays selected to distinguish subjects who respond from those who fail to respond to rituximab treatment. A research team, composed of a transplant surgeon with expertise in immunology and rituximab, adult and pediatric nephrologists with expertise in FSGS, supported by experienced laboratory personnel and clinical study coordinators, has been formed. If successful, this pilot trial would provide new insights into the pathophysiology of FSGS and form the basis for a large clinical trial in this poorly responsive disease.